rs886037775

Variant names:

• chr8-19960948-A-G
• rs886037775
• NM_000237.3:c.1187A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-19960948-A-G
• chr8-19960948-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000237.3(LPL):​c.1187A>G​(p.Glu396Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E396V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LPL NM_000237.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.05
• Publications: 0 publications found

Genes affected

LPL (HGNC:6677): (lipoprotein lipase) LPL encodes lipoprotein lipase, which is expressed in heart, muscle, and adipose tissue. LPL functions as a homodimer, and has the dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia, while less extreme mutations in LPL are linked to many disorders of lipoprotein metabolism. [provided by RefSeq, Jul 2008]

LPL Gene-Disease associations (from GenCC):

• familial lipoprotein lipase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hyperlipidemia, familial combined, LPL related

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr8-19960948-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226450.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Trascript score misZ: -0.36753 (below the threshold of 3.09). GenCC associations: The gene is linked to familial lipoprotein lipase deficiency, hyperlipidemia, familial combined, LPL related.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3	c.1187A>G	p.Glu396Gly	missense_variant	Exon 8 of 10	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1	c.1187A>G	p.Glu396Gly	missense_variant	Exon 8 of 10		NM_000237.3	ENSP00000497642.1
LPL	ENST00000650478.1	n.*10A>G		non_coding_transcript_exon_variant	Exon 2 of 4			ENSP00000497560.1
LPL	ENST00000650478.1	n.*10A>G		3_prime_UTR_variant	Exon 2 of 4			ENSP00000497560.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461780 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111920

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	2.9	M;M
PhyloP100		7.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.0	D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0040	D;.
Sift4G	Benign	0.14	T;.
Polyphen		1.0	D;D
Vest4		0.60
MutPred		0.64		Loss of stability (P = 0.0313);Loss of stability (P = 0.0313);
MVP		0.94
MPC		0.37
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.47
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.40		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886037775; hg19: chr8-19818459;